Stanford gene researchers see diabetes develop

STANFORD

Published 4:00 am, Friday, March 16, 2012

A team of Stanford researchers has unveiled the most detailed biological profile of a human being done so far: a peek at one man's genetic foundation, along with snapshots, taken dozens of times over the course of a year, of the millions of proteins and other molecules that are in constant flux in his body.

In a stroke of shocking good luck - for the scientists, if not necessarily the patient - the profile subject developed Type 2 diabetes during the study, allowing researchers to follow in real time the molecular changes that took place as the illness progressed.

It also allowed the subject, Stanford geneticist Michael Snyder, to catch his diabetes early and stop it, most likely months or even years before he would have been diagnosed without the genetic profiling.

"This is the first time someone's actually analyzed the genome of a healthy person, predicted disease risk, and then by following him, actually saw a disease develop," said Snyder, who in addition to being the subject of the study was the senior author.

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Snyder's profile and an analysis of the results were published today in the journal Cell. Snyder, chairman of the genetics department at Stanford, is not named in the published study because of privacy rules, but he volunteered to identify himself.

The research provides some of the first proof that detailed genetic profiling - beyond just DNA sequencing - could be used someday not just to predict an individual's chances of developing disease, but also to identify the smallest molecular changes that show when a person starts to become ill, said experts in personalized medicine.

Personal mapping

The first human genome - a map of all of the DNA in a human cell - was announced in 2000. Seven or eight years later geneticists began mapping the genomes of specific individuals. Such personal genomic sequencing is expected to become widely available this year, at a cost of several thousand dollars.

Using genetic information to help diagnose and treat patients is still a very new field, although it's growing rapidly. Certain key genes have been found to greatly increase the risk of breast cancer, for example, or the deadly Huntington's disease, and doctors will regularly test for those genes when someone is diagnosed with an illness or when a close family member is known to have a disease.

But for most people, DNA sequencing and other biological profiling isn't yet useful - subjects would end up with a lot of unwieldy information that is mostly beyond modern scientific understanding or far too expensive to analyze.

"What they did (at Stanford) is much more interesting from a scientific basis than a practical basis," said Dr. David Witt, a medical geneticist at Kaiser San Jose. "And that gets to the heart of personalized medicine: It's not ready for prime time."

Clinical use

The Stanford research doesn't change the hurdles to biological profiling, Witt and other genetics experts said. But it does prove that there's value in such profiling if it can be made practical and cost-effective, and that's not something that genetic scientists have been convinced of, said UC Berkeley geneticist Steven Brenner.

"We've known that genetic information would be very important for understanding the molecular basis of diseases, but whether looking at it would be of use to a person has not been totally clear," Brenner said. "This is one of most compelling pieces so far showing interesting things that may be useful in a clinical setting."

Snyder's team of geneticists started the study by mapping his genome. Over 14 months, they also profiled all of the proteins in his body at specific points in time, in addition to the molecules produced during cellular metabolism; antibodies that work against his own cells; and RNA transcripts, which are made during the process of turning DNA into RNA.

It's those genetic snapshots that are unique to this study, and may prove to be even more useful in the field of personalized medicine than just DNA sequencing alone, said Lior Pachter, a comparative genomics researcher at UC Berkeley.

"DNA is static. It might be much more relevant to measure what's actually happening in the molecular biology of a given individual, and not just what in principle could happen," Pachter said.

Signs of disease

Snyder's genomic profile identified right away that he was at increased risk for Type 2 diabetes, as well as a type of anemia, high cholesterol and emphysema. He'd already known about the other risk factors, but the diabetes was a surprise, said Snyder, who was attending a conference in Australia.

An even bigger surprise was when he got a viral infection halfway through the study, and a molecular snapshot showed his body wasn't regulating glucose the way it should. Shortly thereafter, another blood test showed that his insulin levels had increased dramatically, and Snyder went for an exam with his regular doctor. He learned then that he had diabetes.

The study, Snyder said, is the first to find a possible association between Type 2 diabetes and a viral infection, although it's too early to say that the virus is what triggered the diabetes. Still, it suggests an interesting topic of future study, he said.

But in the meantime, he's eager to learn more about his own biological makeup, and to find ways to make such profiling a standard part of medicine.

"The way we do medicine now is woefully inadequate. You go to a doctor's office and they measure less than 20 things," Snyder said. "We should be measuring thousands if not millions of things. In my case we followed tens of thousands of things at a level that nobody's ever seen before. I think that will be the future."

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